As described in Published international application WO 2005/116009 A1 (the '009 publication) and published U.S. patent application no. 2006/0106062 (the '062 publication), each of which was filed on May 16, 2005 (the '009 publication), and each of which is incorporated herein in its entirety by reference, 2-(Quinolin-5-yl)-4,5 Disubstituted-Azole derivatives (Formula I) which have pharmaceutical activity as PDE-4 inhibitor compounds.
wherein:
X is O or S
R1 is H, alkyl, cycloalkyl, cycloalkyl(C1-C4)alkyl-, —CH2F, —CHF2, —CF3, —C(O)alkyl or —C(O)NR18R19;
R2 is —OR* or —N(R7)(R8), wherein R* is linear, branched, or cyclic alkyl or substituted linear, branched, or cyclic alkyl, and R7 and R8 are defined herein below;
R3 and R4 are independently selected from the group consisting of H, alkyl, hydroxyalkyl and —C(O)Oalkyl;
R5a and R6b are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, —CH2F, —CHF2, —CF3, —C(O)OH, —C(O)Oalkyl and —C(O)NR43R44;
t is 1 or 2;
R7 is H, alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, (R17-phenyl)alkyl or —CH2—C(O)—O-alkyl;
R8 is H, alkyl, alkenyl, alkoxy, alkoxyalkyl, hydroxyalkyl, dihydroxyalkyl, alkyl-NR18R19, cyanoalkyl, R23-heteroaryl, R23-heteroarylalkyl, (R36-heterocycloalkyl)alkyl, R17-phenyl, (R17-phenyl)alkyl, R7-naphthyl, (R17-naphthyl)alkyl, R17-benzyloxy, -alkyl-C(O)—NR18R19, -alkyl-C(O)—N(R30)—(R23-heteroaryl), -alkyl-C(O)—N(R30)-(cycloalkyl), -alkyl-C(O)—(R36-heterocycloalkyl); -alkyl-N(R30)—C(O)Oalkyl, -alkyl-N(R30)—C(O)—NR18R19, -alkyl-N(R30)—C(O)alkyl, -alkyl-N(R30)—C(O)-(fluoroalkyl), -alkyl-N(R30)—C(O)—(R39-cycloalkyl), -alkyl-N(R30)—C(O)—(R17-phenyl), -alkyl-N(R30)—C(O)—(R23-heteroaryl), -alkyl-N(R30)—C(O)-alkylene-(R23-heteroaryl), -alkyl-NH—SO2—NR18R19, -alkyl-N(R30)—(R17-phenyl), -alkyl-N(R30)—(R23-heteroaryl), -alkyl-O—(R17-phenyl), -alkyl-O—(R23-heteroaryl), -alkyl-N(R30)—SO2-alkyl, R45-hydroxyalkyl, dihydroxyalkyl substituted by R17-benzyloxy, dihydroxyalkyl substituted by R17-phenyl, alkoxyalkyl substituted by R17-phenyl, (R17-phenyl)alkyl substituted by —CO2alkyl, (R17-phenyl)alkyl substituted by —C(O)NH2, alkyl substituted by (R23-heteroaryl) and —C(O)NR37R38, R12-cycloalkyl, (R12-cycloalkyl)alkyl,

or R7 and R8 and the nitrogen to which they are attached together form a ring system selected from the group consisting of

p is 0 or 1;
q is 0 or 1;
the dotted line represents an optional double bond;
R9 is H, halo, alkyl, cycloalkyl, —CH2F, —CHF2 or CF3;
R10, R11, and R13 are independently selected from the group consisting of H and halo;
R12 is 1-3 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, —C(O)Oalkyl, —(CH2)n—N(R30)—C(O)-cycloalkyl, —(CH2)n—N(R30)—C(O)alkyl, —(CH2)n—N(R30)—C(O)Oalkyl, —(CH2)n—N(R30)—(R23-heteroaryl), —(CH2)n—N(R30)—C(O)—NR18R19 and —(CH2)n—C(O)—NR18R19;
R14 is 1 or 2 substituents independently selected from the group consisting of H, OH, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, —CF3, CN, R17-phenyl, (R17-phenyl)alkyl, —NR18R19, alkyl-NR18R19, —(CH2)n—C(O)OH, —(CH2)n—C(O)Oalkyl, —(CH2)n—C(O)alkyl, —(CH2)n—C(O)(R35-phenyl), —(CH2)n—C(O)(R23-heteroaryl), —(CH2)n—C(O)NR18R19, —(CH2)n—C(O)N(R30)—(CH2)—(R23-heteroaryl), —(CH2)n—N(R30)—C(O)alkyl, —(CH2)n—N(R30)—C(O)-(fluoroalkyl), —(CH2)n—N(R30)—C(O)-(cycloalkyl), —(CH2)n—N(R30)—C(O)(R35-phenyl), —(CH2)n—N(R30)—C(O)(R23-heteroaryl), —(CH2)n—N(R30)C(O)NR18R19, —(CH2)n—N(R30)—C(O)Oalkyl, —(CH2)n—N(R30)cycloalkyl, —(CH2)n—N(R30)(R17-phenyl), —(CH2)n—N(R30)(R23-heteroaryl), —(CH2)n—N(R18)SO2alkyl, —(CH2)n—N(R20)SO2—(R17-phenyl), —(CH2)n—N(R30)SO2—CF3, —CH2S(O)0-2(R35-phenyl), —(CH2)n—OC(O)N(R23)alkyl, R23-heteroaryl, (R23-heteroaryl)alkyl, (R23-heteroaryl)oxy, (R23-heteroaryl)amino, —CH(OH)—(R17-phenyl), —CH(OH)—(R23-heteroaryl), —C(═NOR30)—(R17-phenyl), —C(═NOR30)—(R23-heteroaryl), morpholinyl, thiomorpholinyl,

w is 0 or 1;
or two R14 substituents and the carbon to which they are both attached form —C(═NOR30)— or —C(O)—;
each n is independently 0, 1, 2 or 3;
R15 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, —C(O)Oalkyl, —C(O)O(R30-cycloalkyl), -alkyl-C(O)O-alkyl, —C(O)O-alkylene-(R35-phenyl), R17-phenyl, (R17-phenyl)alkyl, —CH—(R17-phenyl)2, R23-heteroaryl, —(CH2)n—C(O)NR18R19, —SO2-alkyl, —SO2-cycloalkyl, —SO2—CF3, —SO2—(R35-phenyl), —SO2—NR18R19, —C(O)alkyl, —C(O)-(fluoroalkyl), —C(O)—C(CH3)(CF3)2, —C(O)—(R17-phenyl), —C(O)—(R23-heteroaryl), —C(O)-hydroxyalkyl, —C(O)-alkoxyalkyl, —C(O)—(R39-cycloalkyl), —C(O)-alkylene-(R17-phenyl), —C(O)-alkylene-(R23-heteroaryl), —C(O)-alkylene-S—C(O)alkyl, —C(═S)—(R17-phenyl), hydroxyalkyl substituted by R17-phenyl, hydroxyalkyl substituted by R23-heteroaryl, alkoxyalkyl substituted by R17-phenyl, alkoxyalkyl substituted by R23-heteroaryl,
wherein z is 0, 1 or 2;
R16 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, R17-phenyl, (R17-phenyl)alkyl, (R23-heteroaryl)alkyl, hydroxyalkyl, alkoxyalkyl and —C(O)Oalkyl, or two R16 groups and the carbon to which they are both attached form —C(O)—;
R17 represents 1 to 3 substituents replacing a hydrogen on a phenyl moiety, each of which is independently selected from the group consisting of halo, alkyl, cycloalkyl, —OH, hydroxyalkyl, alkoxy, —CN, —CF3, —OCF3, —OCHF2,
—OCH2F, —C(O)OH, —C(O)Oalkyl, —C(O)O—(R35-phenyl), —C(O)alkyl, —C(O)—(R35-phenyl), —SOalkyl, —SO2alkyl, —SO2—CF3, alkylthio, —NR43R44, -alkyl-NR43R44 and heteroaryl; or two R17 substituents on adjacent carbon atoms together form —O—CH2—O—, —O—(CH2)2—O—, —(CH2)2—O— or —O—CH2—O—CH2—;
R18 and R19 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, R17-phenyl and (R17-phenyl)alkyl;
R20 is H, alkyl, or cycloalkyl;
R22 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, halo, —CF3, —NH2 and R35-phenyl;
R23 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, hydroxy, alkoxy, halo, —CF3, —NR18R19, —CN, —C(O)Oalkyl, —NHSO2-alkyl and R35-phenyl;
R24 is H, OH or alkoxy; or when the optional double bond is present, R24 and the adjacent carbon atom form the double bond;
R25 is H or R35 phenyl;
R27 is 1 to 3 substituents independently selected from the group consisting of H, halo, OH, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, —CF3, —CN, —C(O)OH,
—C(O)Oalkyl, —C(O)N(R30)(R18), —C(O)—(R36-heterocycloalkyl), R17-phenyl, (R17-phenyl)-alkyl, R23-heteroaryl, (R23-heteroaryl)alkyl, (R23-heteroaryl)oxy, (R23-heteroaryl)amino NR18R19, NR18R19-alkyl, —(CH2)n—N(R30)—C(O)alkyl, —(CH2)n—N(R30)—C(O)-(fluoroalkyl), —(CH2)n—N(R30)—C(O)alkoxyalkyl, —(CH2)n—N(R30)—C(O)(cycloalkyl), —(CH2)n—N(R30)—(R23-heteroaryl), —(CH2)n—N(R30)—C(O)—(R23-heteroaryl), —(CH2)n—N(R30)—C(O)O-alkyl, —(CH2)n—N(R30)—C(O)O—(CF3-alkyl), —(CH2)n—N(R30)—C(O)O—(R39-cycloalkyl), —(CH2)n—N(R30)—C(O)O-alkylene-cycloalkyl, —(CH2)n—N(R30)—C(O)—N(R30)(R20), —(CH2)n—N(R30)—SO2-alkyl, —(CH2)n—N(R30)—SO2—CF3, —(CH2)n—N(R30)—SO2—N(R30)2 and

or two R27 groups and the carbon to which they are both attached form —C(═NOR30)— or —C(O)—;
R28 is H, alkyl, R35-benzyl or -alkyl-C(O)O-alkyl;
R29 is alkyl, —C(O)Oalkyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)—(R17-phenyl), —C(O)—(R23-heteroaryl), —SO2-alkyl, —SO2—(R35-phenyl), —C(O)NR18R19, R35-phenyl, (R35-phenyl)alkyl or R23-heteroaryl;
R30 is independently selected from the group consisting of H, alkyl and R35-benzyl;
R31 is H, alkyl, R35-benzyl or phenoxyalkyl;
R33 is H, OH or alkoxy;
R34 is H, alkyl, hydroxyalkyl, alkoxyalkyl or —C(O)Oalkyl;
R35 is 1 to 3 substituents independently selected from the group consisting of H, halo, alkyl, OH, —CF3 and alkoxy;
R36 is 1 or 2 substituents independently selected from the group consisting of H, alkyl, R17-phenyl, alkoxyalkyl and —C(O)Oalkyl; or two R36 groups and the carbon to which they are both attached form —C(═NOR30)— or —C(O)—;
R37 and R38 are independently selected from the group consisting of H and alkyl, or R37 and R38 together are —(CH2)3— or —(CH2)4—, and together with the nitrogen to which they are attached, form a ring;
R39 is H, OH, alkyl, alkoxy, or CF3;
R40 is —OR30 or —NHC(O)alkyl;
R41 is H or —SO2alkyl;
R42 is —(CH2)n—(R35-phenyl), —(CH2)n—(R23-heteroaryl), —C(O)Oalkyl or —C(O)alkyl;
R43 and R44 are independently selected from the group consisting of H and alkyl; and
R45 is 1 or 2 substituents independently selected from the group consisting of halo, alkoxyalkyl, —CO2alkyl, R17-phenyl, R23-heteroaryl and cycloalkyl.
Compounds of Formula I can be prepared using synthesis procedures and synthetic schemes described in the above-referenced published applications, for example, on pages 25 to 32 of the '009 publication, and exemplified throughout the '062 and '009 publications. One example is the synthetic scheme shown on pages 26 to 28 of the '009 publication, summarized below as Scheme I.

Compounds of Formula I of particular interest include the compounds having the structure of Formulae IXaa and IXab (below),

Processes for preparing these compounds are described in, for example, published US patent application No. 2006/0106062 A1, published May 18, 2006 (the above-described '062 publication). In particular, the '062 publication describes a batch process for the preparation of the compound of Formula IXaa on pages 83 to 86 (preparative Examples 5 to 7, in preparation of the example compound 26-347, which is illustrated on page 193) and a process for the preparation of the compound of Formula IXab on pages 380 to 382 (preparative Examples 8 to 11 in preparation of the example compound 38-8, which is illustrated on page 383), each of which process is incorporated by reference herein in its entirety, and each of which is next described in further detail.
In addition, the compound of Formula IXab has been prepared in accordance with Scheme Ia.

With reference to Scheme Ia, preparation of the tri substituted oxazole of Formula Ia2-ester, by treatment of the compound of Formula Ia1 with the acid halide of Formula Ib1, or its related acid (Ia2-acid) prepared by hydrolyzing the ester functional group of the oxazole of Formula Ia2-ester, provides a product which contains high levels of unwanted side reaction products and shows poor utilization of the starting materials.
In the same manner, the compound of Formula IXaa can be prepared in accordance with Scheme Iaa, as described in the above-reference '009 publication beginning on page 145, Example 8 therein, and with reference to synthesis schemes on pages 26 and 27 therein.

As will be appreciated from the foregoing, a key step in the synthesis of PDE IV compounds of Formula I is illustrated in Scheme Ib (below), and shown in Step 2 in any of Synthesis Schemes I, Ia, and Iaa, which is the formation of an oxazole ring by acylating a quinolinyl intermediate compound, with reference to Scheme Ib, compound 10, using an acid fluoride acylating reagent (11) to provide the oxazoline-substituted quinoline compound (IV).

As described in the '009 publication, and illustrated in Scheme Ic, below, the acid fluoride acylating reagents (11), for example, with reference to Scheme Iaa, step 2, the compound of Formula 18a, wherein R3 and R5 are hydrogen, R4 is t-BOC, and R6 is t-butoxymethyl-, that are necessary to prepare these critical intermediates in accordance with these schemes are themselves prepared by treating the corresponding acid with toxic, unstable cyuranic fluoride (9), as illustrated in Scheme Ic.

As will be appreciated, when the acylating reagent is to be provided from an acid which contains functional groups that may be sensitive to unwanted side reactions under the conditions used to prepare the acylating reagent or under the acylation conditions, the sensitive functionality is converted to a protecting group before the fluorination and/or subsequent acylation reactions are carried out. This method requires handling of a hazardous and toxic reagent, the cyuranic fluoride. In addition to being a hazardous material, cyuranic fluoride is not available in lot quantities of a size suitable for commercial scale preparation of the acid fluoride intermediate.